C3-dependent mechanism of microglial priming relevant to multiple sclerosis

Abstract

Microglial priming predisposes the brain to neurodegeneration and affects disease progression. The signal to switch from the quiescent to the primed state is unknown. We show that deleting the C3 convertase regulator complement receptor 1-related protein y (Crry) induces microglial priming. Mice that were double-knockout for Crry and either C3 or factor B did not show priming, demonstrating dependence on alternative pathway activation. Colocalization of C3b/ iC3b and CR3 implicated the CR3/iC3b interaction in priming. Systemic lipopolysaccharide challenge overactivated primed microglia with florid expression of proinflammatory molecules, which were blocked by complement inhibition. Relevance for neurodegenerative disease is exemplified by human multiple sclerosis (MS) and by experimental autoimmune encephalomyelitis (EAE), a model of MS. In human MS, microglial priming was evident in perilesional white matter, in close proximity to C3b/iC3b deposits. EAE was accelerated and exacerbated in Crry-deficient mice, and was dependent on C activation. In summary, C3-dependent microglial priming confers susceptibility to other challenges. Our observations are relevant to progression in MS and other neurological diseases exacerbated by acute insults.

Uncovering the Path to Neurodegeneration from Playingfield to Battlefield

“…For example, in vitro studies have shown that exposure to Aβ primes microglia to produce an exaggerated respiratory burst during phagocytosis [120]. In addition, our group has recently shown that deposition of activated complement proteins, known to opsonize damaged axons after trauma [9,11], can also regulate the microglial phenotype [8,121]. In mice, deletion of the major regulator of the C3 convertase, Crry, induces deposition of active C3 in tissue and induces microglia priming, likely by binding to complement receptor 3 (CD11b/CD14) on microglia.…”

“…Our effort over the past 10 years has been directed to study the role of the complement cascade in the nervous system [8][9][10][11][12][13][14]. To date we have collected evidence which support a role for complement in microglia priming [8] as well as the protective role of inhibitors of complement activation in nerve damage [10,13].…”

“…According to our hypothesis, microglia in the traumatized brain are sensitized to respond more vigorously to a subsequent injurious event. This phenomenon is named microglia priming [8]. Primed microglia are in a "ready-to-go" state which, if triggered by a challenge -for example a systemic infection, surgery or vaccination occurring even later in life -, may outburst in a severe pro-inflammatory event which results in prolonged delirium and cognitive deficit.…”

“…To date we have collected evidence which support a role for complement in microglia priming [8] as well as the protective role of inhibitors of complement activation in nerve damage [10,13]. Therefore, in this chapter we focus on the complement system as a potential target for therapy to fight neurodegeneration.…”

Human Skin Mast Cells Express Complement Factors C3 and C5

“…Locally synthesized C3 and C5, presumably through their bioactive metabolites, importantly regulate other aspects of inflammation and host defense (42,43), for example, clearance of immune complexes by macrophages (44). As studied with APCs in murine systems, C3 and C5 affect expression of costimulatory molecules in an autocrine manner and T cell development in a paracrine manner (41,(45)(46)(47)(48), thereby modulating murine immunity along with models of inflammatory bowel disease (49), multiple sclerosis (50), and graft-versus-host disease (10). These studies show the importance of locally produced and activated complement proteins.…”